Green aldose isomerisation: 2-C-methyl-1,4-lactones from the reaction of Amadori ketoses with calcium hydroxide

Saccharinic acids, branched 2-C-methyl-aldonic acids, may be accessed via a green procedure from aldoses by sequential conversion to an Amadori ketose and treatment with calcium hydroxide; d-galactose and d-glucose are converted to 2-C-methyl-d-lyxono-1,4-lactone (with a small amount of 2-C-methyl-d-xylono-1,4-lactone) and 2-C-methyl-d-ribono-1,4-lactone. Inversion of configuration at C-4 of the branched lactones allows access to 2-C-methyl-l-ribono-1,4-lactone and 2-C-methyl-l-lyxono-1,4-lactone, respectively. d-Xylose affords 2-C-methyl-d-threono-1,4-lactone and 2-C-methyl-d-erythrono-1,4-lactone, whereas l-arabinose, under similar conditions, gave the enantiomers 2-C-methyl-l-threono-1,4-lactone and 2-C-methyl-l-erythrono-1,4-lactone.     

Dinucleotides of 4′-C-vinyl- and 5′-C-allylthymidine as substrates for ring-closing metathesis reactions

Thymidine derivatives containing a 4′-C-vinyl group or a 5′-C-allyl group are synthesized and used as building blocks for three different dinucleotides. These are evaluated as substrates for ring-closing metathesis cyclisations, and a protected 5′-C-allylthymidine homo-dimer is found to be the most reactive. A protected precursor for a conformationally restricted cyclic dinucleotide with a four carbon 5′-C to 5′-C connection is hereby efficiently obtained, whereas a corresponding three carbon 4′-C to 5′-C connection is obtained in a lower yield.     

(3R,4S)-3,4,5-Trihydroxy-4-methylpentylphosphonic acid, an isosteric phosphonate analogue of 2-C-methyl-d-erythritol 4-phosphate, a key intermediate in the new pathway for isoprenoid biosynthesis

2-C-Methyl-d-erythritol 4-phosphate (MEP) is the first intermediate in the mevalonate-independent pathway for isoprenoid biosynthesis presenting the branched C₅ isoprene skeleton. Enantiopure (3R,4S)-3,4,5-trihydroxy-4-methylpentylphosphonic acid (MEP_N), an isosteric phosphonate analogue of MEP was synthesized from 1,2-O-isopropylidene-α-d-xylofuranose.     

A convenient synthesis of 2-C-methyl-d-erythritol 4-phosphate and isotopomers of its precursor

A new synthetic approach toward 2-C-methyl-d-erythritol 4-phosphate (MEP), a key intermediate in the mevalonate-independent biosynthetic pathway for isoprenoids, and deuterated analogues of its precursor, 2-C-methyl-d-erythritol acetonide, is described. This procedure uses 2-C-methyl-d-erythrose acetonide as starting material and delivers, through a mono-protection strategy, the target compounds in a short way and in high yield.     

Stereoselective synthesis of 4-C-methyl-2,3,5-tri-O-benzyl-d-ribofuranose and 4-C-methyl-2,3,5-tri-O-benzyl-l-lyxofuranose

Sugar intermediates 4-C-methyl-2,3,5-tri-O-benzyl-d-ribofuranose (8b) and 4-C-methyl-2,3,5-tri-O-benzyl-l-lyxofuranose (8a) were synthesized by addition of alkylithium reagents to pentanones 3a,b. The nucleophilic additions proceeded with good stereoselectivity and good yields to give the titled compounds in four steps from perbenzylated methyl d-ribofuranoside and methyl 5′-deoxy-d-ribofuranoside.     

Synthesis of 4′,4′-C-diaminomethyl nucleoside derivative as a building block for constructing libraries via amide bond formation

Preparation of the 4′,4′-C-diaminomethyl uridine analog starting from the commercial uridine via 4′,4′-C-dihydroxymethyl uridine, 4′,4′-C-bis-trifluoromethanesulfonyloxymethyl uridine, and 4′,4′-C-diazidomethyl uridine in total eight steps was achieved in 8% yield. Steric hindrance between 3′-O-TBDMS and 5′-O-triflate prevented the undesired ring closure which made the synthesis of target compound feasible.     

Anomeric stereospecific synthesis of 2′-C-methyl β-nucleosides; the Holy reaction of cyanamide with 2-C-methyl-d-arabinose

The sequential reactions of 2-C-methyl-d-arabinose with cyanamide and methyl propiolate afford an anhydronucleoside, which may be opened under acid conditions with inversion at C2′, to give 2′-C-methyl uridine; ring opening with sodium hydroxide gave 2′-C-methyl arabino-uridine with retention of configuration at C2′. This gives complete stereospecific control to yield only β-nucleosides.     

Chiral 2-C-methylene glycosides and carbohydrate-derived pyrano[2,3-b][1]benzopyrans: synthesis via InCl3 catalyzed stereoselective Ferrier rearrangement of 2-C-acetoxymethyl glycal derivatives

2-C-Acetoxymethyl glycal derivatives react with aliphatic alcohols in the presence of InCl₃ (30 mol %) to furnish the corresponding 2-C-methylene glycosides in excellent yields and with exclusive α-selectivity except for the methyl 2-C-methylene glycosides, which are formed in ∼2:1 anomeric ratio in favour of the α-anomer. The reaction of 2-C-acetoxyglycals with phenols, however, produces the corresponding chiral carbohydrate-derived pyranobenzopyran derivatives via initial Ferrier rearrangement followed by tandem cyclization in excellent yields and moderate to high stereoselectivities in favour of the corresponding 10a-R-pyrano[2,3-b][1]benzopyran derivatives.     

Syntheses of 2′-C-amidoalkyl and 2′-C-cyanoalkyl containing oligodeoxyribonucleotides and assessment of their hybridisation affinity for complementary DNA and RNA

Oligodeoxynucleotides containing 2′-C-branched nucleosides with an amide or nitrile appended to either a one or two carbon alkyl chain have been synthesised. The phosphoramidites of the 2′-C-modified nucleosides were prepared and incorporated into the oligonucleotides using automated DNA synthesis. The duplex stability with complementary RNA and DNA was measured by UV melting experiments, in order to assess whether the amide/nitrile function could induce any duplex stability without the presence of the 2′-oxygen. The duplex stabilities of the oligonucleotides containing the 2′-C-modifications were decreased in the absence of the 2′-oxygen.     

Hydroxylated C-branched pyrrolidines, C-branched prolines and C-branched piperidines from a 2-C-methyl sugar lactone; efficient azide displacement of a tertiary triflate with inversion of configuration

The versatility of 3,4-O-isopropylidene-2-C-methyl-d-arabinonolactone [from d-erythronolactone] as a chiron for complex piperidines and pyrrolidines is illustrated by the synthesis of (2R,3S,4S)- and (2R,3S,4R)-dihydroxy-2-C-methyl prolines, 1,4-dideoxy-1,4-imino-4-C-methyl-l-ribitol and 1,4-dideoxy-1,4-imino-4-C-methyl-l-arabinitol, and isofagomine derivatives; the enantiomeric series is equally accessible from l-erythronolactone.     

Doubly carbon-branched pentoses: synthesis of both enantiomers of 2,4-di-C-methyl arabinose and 2-deoxy-2,4-di-C-methyl arabinose using only acetonide protection

An acetonide is the only protecting group used in the synthesis of both the enantiomers of 2,4-di-C-methyl arabinose and 2-deoxy-2,4-di-C-methyl arabinose via the enantiomeric 3-C-methyl-l-erythronolactone [from 2-C-methyl-d-ribono-lactone or d-ribose] and 3-C-methyl-d-erythronolactone [from d-tagatose or l-ribose]. NMR studies on unprotected C-methyl arabinoses show that methyl branching significantly affects the ratios of pyranose and furanose forms present in aqueous solution.     

Homochiral carbon branched piperidines from carbon branched sugar lactones: 4-C-methyl-deoxyfuconojirimycin (DFJ) and its enantiomer—removal of glycosidase inhibition

The value of readily available 2-C-methyl aldonic acids in short syntheses of carbon branched piperidines containing quaternary centers is demonstrated. The effect of the introduction of a 4-C-methyl group into piperidine imino sugar inhibitors of l-fucosidases and d-galactosidases is reported.     

Stereocontrolled synthesis of anthracene β-C-ribosides: fluorescent probes for photophysical studies of DNA

Effective, stereocontrolled syntheses of the 1-anthracenyl and 2-anthrancenyl β-C-2′-deoxyribosides are reported and were based on a diastereofacialselective, palladium-catalyzed glycosidation of the corresponding protected (4S,5R)-4-hydroxy-5-(hydroxymethyl)dihydrofuran.     

Diastereoselective synthesis of 5-(alditol-1-C-yl)-hydantoins and their use as precursors of polyhydroxylated-α-amino acids

The synthesis of 5-(alditol-1-C-yl)-hydantoin derivatives was performed via diastereoselective aldol-type addition of 1,3-dibenzyl-hydantoin to enantiopure aldehydo sugars. Starting from the d-ribo-configured 5-(alditol-1-C-yl)-hydantoin template, the synthesis of (2R,3S,4R)-3,4,5-trihydroxynorvaline was carried out.     

Stereoselective synthesis of 2-C-methylene glycosides and disaccharides via direct allylic substitution of hydroxy group in benzylated glycals

InCl₃ efficiently catalyzes allylic substitution of the hydroxy group of 2-C-hydroxymethyl glycals to afford a diversity of 2-C-methylene alkyl and aryl glycosides as well as disaccharides in high yields. This protocol surpasses the existing methods for the synthesis of 2-C-methylene glycosides as it obviates the need for functionalizing the allylic hydroxy group of glycals. The interest of this methodology relies on the extremely mild conditions required even with a free hydroxyl group at the allylic position of the glycals and that too only with a catalytic amount of InCl₃. The reaction is fast (30 min.), stereoselective and is compatible with a variety of oxygenated nucleophiles including those possessing acid-labile groups. A mechanistic investigation on the direct formation of an α,α-(1→1)linked disaccharide derivative from 2-C-hydroxymethyl galactal reveals that the reaction proceeds through a domino Ferrier rearrangement followed by a facile 1,3-alkoxy migration.     

Facile synthesis of 2-(β-C-glucopyranosyl)-β-amino acid: a new class of glycopeptide building block

A convenient preparation of both stereoisomers of a (2R)/(2S)-2-C-glycosylated β-amino acid is described. β-C-Glycoside was formed by the reaction of α-acetobromoglucose with carbanion of cyanoacetate. The steric bulk of the C-glycoside moiety does not hinder amino acid coupling, showing the utility of this carbohydrate-containing building block for glycopeptide synthesis.     

Synthesis and protein reactivity of 2E,4E,6E-dodecatrienal

An efficient approach for synthesis of the food odorant 2E,4E,6E-dodecatrienal (DTE) by extension of 2E,4E-decadienal (DDE) is reported. DTE shows higher protein crosslinking ability than the lipid peroxidation products DDE and 4-hydroxy-2E-nonenal.     

Synthesis of 3′-deoxy-3′-C-methyl-β-d-ribonucleoside analogs

3′-Deoxy-3′-C-methyl-β-d-ribonucleoside analogs bearing the five canonical bases of nucleic acids have been synthesized. All these derivatives were prepared by glycosylation of the corresponding heterocyclic bases with a suitable peracylated 3-C-methyl sugar precursor. The synthesis of the 3-C-methyl sugar precursor is described following a new stereoselective synthetic pathway.     

HSAB-driven regioselectivity difference in the Lewis-acid catalyzed reactions of 2-C-substituted glycals with sulfur and oxygen nucleophiles: direct versus allylic substitution

A remarkable regioselectivity difference in the Lewis-acid catalyzed reactions of 2-C-acteoxymethyl glycals with thiophenols and phenols has been observed. The reaction with thiophenols led to preferential formation of a new class of compounds viz. 2-C-arylthiomethyl glycals via direct attack at the C-2 side chain primary carbon bearing the leaving group. In contrast, phenols were reported to afford predominantly 2-C-methylene-O-aryl glycosides via allylic attack at the anomeric carbon. The observed results correlate well with the HSAB principle proposed earlier for similar type of reactions with simple glycals. In addition, formation of an unusual bis-thioarylated product in presence of an excess of thiophenol is also reported.     

Synthesis of 1-C-alkyl-α-d-glucopyranosides by Lewis acid- or Brønsted acid-catalyzed O-glycosidation

We prepared several kinds of 1-C-alkyl-2,3,4,6-tetra-O-benzyl-α-d-glucopyranose derivatives containing methyl, ethyl, n-butyl, and benzyl groups as the alkyl groups at their anomeric positions. The Lewis acid- or Brønsted acid-catalyzed O-glycosidations using them as the glycosyl donors to synthesize 1-C-alkyl-d-glucopyranosides were investigated. Using 10 mol % of triphenylmethyl perchlorate efficiently catalyzed the glycosidation of 2,3,4,6-tetra-O-benzyl-1-C-methyl-α-d-glucopyranosyl dimethylphosphinothioate. The glycosidation using the 1-C-alkyl-2,3,4,6-tetra-O-benzyl-α-d-glucopyranosyl acetates smoothly proceeded in the presence of only 5 mol % of scandium(III) trifluoromethanesulfonate. The dehydration-condensation type glycosidation using the 1-C-alkyl-2,3,4,6-tetra-O-benzyl-α-d-glucopyranoses was significantly promoted using 5 mol % of bis(trifluoromethane)sulfonimide. These glycosidations successfully afforded various 1-C-alkyl-α-d-glucopyranosides in good yields with high α-stereoselectivities.